MAP3K5

Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. MAPKKK5 contains 1,374 amino acids with all 11 kinase subdomains. Northern blot analysis shows that MAPKKK5 transcript is abundantly expressed in human heart and pancreas. The MAPKKK5 protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; MAPKKK5 does not activate MAPK/ERK. [provided by RefSeq]

mitogen-activated protein kinase kinase kinase 5

Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signaling for determination of cell fate such as differentiation and survival. Plays a crucial role in the apoptosis signal transduction pathway through mitochondria-dependent caspase activation. MAP3K5/ASK1 is required for the innate immune response, which is essential for host defense against a wide range of pathogens. Mediates signal transduction of various stressors like oxidative stress as well as by receptor-mediated inflammatory signals, such as the tumor necrosis factor (TNF) or lipopolysaccharide (LPS). Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K4/SEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs and c-jun N-terminal kinases (JNKs). Both p38 MAPK and JNKs control the transcription factors activator protein-1 (AP-1).

Apoptotic signaling pathwayManual Assertion Based On ExperimentTAS:ProtInc
Cellular response to amino acid starvationManual Assertion Based On ExperimentIDA:CAFA
Cellular response to hydrogen peroxideManual Assertion Based On ExperimentIDA:BHF-UCL
Cellular response to reactive nitrogen speciesIEA:Ensembl
Cellular response to tumor necrosis factorIEA:Ensembl
Cellular senescenceTAS:Reactome
Endothelial cell apoptotic processIEA:Ensembl
Innate immune responseIEA:UniProtKB-KW
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stressISS:ParkinsonsUK-UCL
Intrinsic apoptotic signaling pathway in response to oxidative stressManual Assertion Based On ExperimentIDA:UniProtKB
JNK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
MAPK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
p38MAPK cascadeIEA:Ensembl
Positive regulation of apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of cardiac muscle cell apoptotic processIEA:Ensembl
Positive regulation of cysteine-type endopeptidase activity involved in apoptotic processManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of JNK cascadeISS:ParkinsonsUK-UCL
Positive regulation of JUN kinase activityManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Positive regulation of myoblast differentiationIEA:Ensembl
Positive regulation of neuron deathManual Assertion Based On ExperimentIGI:ParkinsonsUK-UCL
Positive regulation of p38MAPK cascadeIEA:Ensembl
Positive regulation of protein kinase activityManual Assertion Based On ExperimentIDA:BHF-UCL
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIDA:CAFA
Positive regulation of vascular associated smooth muscle cell proliferationIEA:Ensembl
Programmed necrotic cell deathIEA:Ensembl
Protein phosphorylationManual Assertion Based On ExperimentIDA:CAFA
Response to endoplasmic reticulum stressManual Assertion Based On ExperimentIMP:ParkinsonsUK-UCL
Response to ischemiaIEA:Ensembl
Stress-activated MAPK cascadeManual Assertion Based On ExperimentIDA:CAFA
Wound healingIEA:Ensembl

Cytoplasm
Endoplasmic reticulum
Interaction with 14-3-3 proteins alters the distribution of MAP3K5/ASK1 and restricts it to the perinuclear endoplasmic reticulum region.

Phosphorylated at Thr-838 through autophosphorylation and by MAP3K6/ASK2 which leads to activation. Thr-838 is dephosphorylated by PPP5C. Ser-83 and Ser-1033 are inactivating phosphorylation sites, the former of which is phosphorylated by AKT1. Phosphorylated at Ser-966 which induces association of MAP3K5/ASK1 with the 14-3-3 family proteins and suppresses MAP3K5/ASK1 activity. Calcineurin (CN) dephosphorylates this site. Also dephosphorylated and activated by PGAM5. Phosphorylation at Ser-966 in response to oxidative stress is negatively regulated by PPIA/CYPA (PubMed:26095851).
Ubiquitinated (PubMed:16038411, PubMed:17220297, PubMed:29186683).
Tumor necrosis factor (TNF) induces TNFR2-dependent ubiquitination, leading to proteasomal degradation (PubMed:17220297).
Ubiquitinated by RC3H2 in a TRIM48-dependent manner (PubMed:29186683).
Methylation at Arg-78 and Arg-80 by PRMT1 promotes association of MAP3K5 with thioredoxin and negatively regulates MAP3K5 association with TRAF2, inhibiting MAP3K5 activation (PubMed:22095282).
Methylation is blocked by ubiquitination of PRMT1 by TRIM48 (PubMed:29186683).